The substances used in the combination according to the invention are, on the one hand, N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, its pharmacologically tolerable salts or its N-oxide [═N-(3,5-dichloro-1-oxypyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide], all of them PDE4 inhibitors, which are described in the international application WO 95/01338 and, on the other hand, known active compounds from the class of PDE3 inhibitors.
Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are ubiquitous intracellular second messengers which are involved in many biological processes which are induced by a huge variety of extracellular stimulants. The inactivation (metabolization) of cAMP and cGMP is effected by enzymes of the cyclic nucleotide phosphodiesterase (PDE) type. At least nine different families of PDE isoenzymes have meanwhile been identified (PDE1 to PDE9).
The PDE3 and PDE4 isoenzyme families caused particular interest; a definitive role in the inactivation of cAMP is ascribed to both. Inhibitors of these isoenzymes exhibit actions on the airways, on the peripheral blood pressure, on the central nervous system (e.g. increase in respiratory rates) and antiinflammatory actions.
The effect on the airways is essentially ascribed to the inhibition of PDE3 and, to a minor extent, also to the inhibition of PDE4. The effects on the blood pressure is regarded as mediated by PDE3, while the anti-inflammatory action and the action on the central nervous system are assigned to the inhibition of PDE4.
The combined use of the PDE4 inhibitor N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide, its pharmacologically tolerable salts or its N-oxide with a PDE3 inhibitor in the sense according to the invention has still not been described in the prior art.